LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription in differentiated cells

Gary LeRoy; Ozgur Oksuz; Nicolas Descostes; Yuki Aoi; Rais A. Ganai; Havva Ortabozkoyun Kara; Jia Ray Yu; Chul Hwan Lee; James Stafford; Ali Shilatifard; Danny Reinberg

doi:10.1126/sciadv.aay3068

LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription in differentiated cells

Gary LeRoy, Ozgur Oksuz, Nicolas Descostes, Yuki Aoi, Rais A. Ganai, Havva Ortabozkoyun Kara, Jia Ray Yu, Chul Hwan Lee, James Stafford, Ali Shilatifard, Danny Reinberg^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

FACT (facilitates chromatin transcription) is a protein complex that allows RNA polymerase II (RNAPII) to overcome the nucleosome-induced barrier to transcription. While abundant in undifferentiated cells and many cancers, FACT is not abundant or is absent in most tissues. Therefore, we screened for additional proteins that might replace FACT upon differentiation. We identified two proteins, lens epithelium-derived growth factor (LEDGF) and hepatoma-derived growth factor 2 (HDGF2), each containing two high mobility group A (HMGA)–like AT-hooks and a methyl-lysine reading Pro-Trp-Trp-Pro (PWWP) domain that binds to H3K36me2 and H3K36me3.LEDGF and HDGF2 colocalize with H3K36me2/3 at genomic regions containing active genes. In myoblasts, LEDGF and HDGF2 are enriched on most active genes. Upon differentiation to myotubes, LEDGF levels decrease, while HDGF2 levels are maintained. Moreover, HDGF2 is required for their proper expression. HDGF2 knockout myoblasts exhibit an accumulation of paused RNAPII within the transcribed region of many HDGF2 target genes, indicating a defect in early elongation.

Original language	English (US)
Article number	eaay3068
Journal	Science Advances
Volume	5
Issue number	10
DOIs	https://doi.org/10.1126/sciadv.aay3068
State	Published - Oct 2 2019

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title = "LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription in differentiated cells",

abstract = "FACT (facilitates chromatin transcription) is a protein complex that allows RNA polymerase II (RNAPII) to overcome the nucleosome-induced barrier to transcription. While abundant in undifferentiated cells and many cancers, FACT is not abundant or is absent in most tissues. Therefore, we screened for additional proteins that might replace FACT upon differentiation. We identified two proteins, lens epithelium-derived growth factor (LEDGF) and hepatoma-derived growth factor 2 (HDGF2), each containing two high mobility group A (HMGA)–like AT-hooks and a methyl-lysine reading Pro-Trp-Trp-Pro (PWWP) domain that binds to H3K36me2 and H3K36me3.LEDGF and HDGF2 colocalize with H3K36me2/3 at genomic regions containing active genes. In myoblasts, LEDGF and HDGF2 are enriched on most active genes. Upon differentiation to myotubes, LEDGF levels decrease, while HDGF2 levels are maintained. Moreover, HDGF2 is required for their proper expression. HDGF2 knockout myoblasts exhibit an accumulation of paused RNAPII within the transcribed region of many HDGF2 target genes, indicating a defect in early elongation.",

author = "Gary LeRoy and Ozgur Oksuz and Nicolas Descostes and Yuki Aoi and Ganai, {Rais A.} and Kara, {Havva Ortabozkoyun} and Yu, {Jia Ray} and Lee, {Chul Hwan} and James Stafford and Ali Shilatifard and Danny Reinberg",

note = "Funding Information: We thank L. Vales for critical guidance and reading of the manuscript. We thank other members (past and present) of Reinberg Laboratory for discussion as the work was in progress. We are also grateful to D. Hernandez for technical assistance. Human MBs were obtained as a gift from the Blau Laboratory (Stanford University) and thanks to S.A. Marshall and E.J. Rendleman for help with PRO-seq NGS (Northwestern University). : This work was supported by grants to D.R. from NIH (R01CA199652) and HHMI. G.L. was partially supported by a grant from the Making Headway Foundation (189290). R.A.G. was supported by the Swedish Society for Medical Research. H.O.K. was supported by a fellowship from the NIH (F31HD090892). J.-R.Y. is supported by the American Cancer Society (PF-17-035-01). J.S. was a Simons Foundation{\textquoteright}s Junior Fellow and is also supported by an NIH (K99AA024837) grant. Publisher Copyright: Copyright {\textcopyright} 2019 The Authors.",

year = "2019",

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doi = "10.1126/sciadv.aay3068",

language = "English (US)",

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T1 - LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription in differentiated cells

AU - LeRoy, Gary

AU - Oksuz, Ozgur

AU - Descostes, Nicolas

AU - Aoi, Yuki

AU - Ganai, Rais A.

AU - Kara, Havva Ortabozkoyun

AU - Yu, Jia Ray

AU - Lee, Chul Hwan

AU - Stafford, James

AU - Shilatifard, Ali

AU - Reinberg, Danny

N1 - Funding Information: We thank L. Vales for critical guidance and reading of the manuscript. We thank other members (past and present) of Reinberg Laboratory for discussion as the work was in progress. We are also grateful to D. Hernandez for technical assistance. Human MBs were obtained as a gift from the Blau Laboratory (Stanford University) and thanks to S.A. Marshall and E.J. Rendleman for help with PRO-seq NGS (Northwestern University). : This work was supported by grants to D.R. from NIH (R01CA199652) and HHMI. G.L. was partially supported by a grant from the Making Headway Foundation (189290). R.A.G. was supported by the Swedish Society for Medical Research. H.O.K. was supported by a fellowship from the NIH (F31HD090892). J.-R.Y. is supported by the American Cancer Society (PF-17-035-01). J.S. was a Simons Foundation’s Junior Fellow and is also supported by an NIH (K99AA024837) grant. Publisher Copyright: Copyright © 2019 The Authors.

PY - 2019/10/2

Y1 - 2019/10/2

N2 - FACT (facilitates chromatin transcription) is a protein complex that allows RNA polymerase II (RNAPII) to overcome the nucleosome-induced barrier to transcription. While abundant in undifferentiated cells and many cancers, FACT is not abundant or is absent in most tissues. Therefore, we screened for additional proteins that might replace FACT upon differentiation. We identified two proteins, lens epithelium-derived growth factor (LEDGF) and hepatoma-derived growth factor 2 (HDGF2), each containing two high mobility group A (HMGA)–like AT-hooks and a methyl-lysine reading Pro-Trp-Trp-Pro (PWWP) domain that binds to H3K36me2 and H3K36me3.LEDGF and HDGF2 colocalize with H3K36me2/3 at genomic regions containing active genes. In myoblasts, LEDGF and HDGF2 are enriched on most active genes. Upon differentiation to myotubes, LEDGF levels decrease, while HDGF2 levels are maintained. Moreover, HDGF2 is required for their proper expression. HDGF2 knockout myoblasts exhibit an accumulation of paused RNAPII within the transcribed region of many HDGF2 target genes, indicating a defect in early elongation.

AB - FACT (facilitates chromatin transcription) is a protein complex that allows RNA polymerase II (RNAPII) to overcome the nucleosome-induced barrier to transcription. While abundant in undifferentiated cells and many cancers, FACT is not abundant or is absent in most tissues. Therefore, we screened for additional proteins that might replace FACT upon differentiation. We identified two proteins, lens epithelium-derived growth factor (LEDGF) and hepatoma-derived growth factor 2 (HDGF2), each containing two high mobility group A (HMGA)–like AT-hooks and a methyl-lysine reading Pro-Trp-Trp-Pro (PWWP) domain that binds to H3K36me2 and H3K36me3.LEDGF and HDGF2 colocalize with H3K36me2/3 at genomic regions containing active genes. In myoblasts, LEDGF and HDGF2 are enriched on most active genes. Upon differentiation to myotubes, LEDGF levels decrease, while HDGF2 levels are maintained. Moreover, HDGF2 is required for their proper expression. HDGF2 knockout myoblasts exhibit an accumulation of paused RNAPII within the transcribed region of many HDGF2 target genes, indicating a defect in early elongation.

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LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription in differentiated cells

Abstract

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